Myelin repair: the role of stem and precursor cells in multiple sclerosis

Abstract

Multiple sclerosis is the most common potential cause of neurological disability in young adults. The disease has two distinct clinical phases, each reflecting a dominant role for separate pathological processes: inflammation drives activity during the relapsing-remitting stage and axon degeneration represents the principal substrate of progressive disability. Recent advances in disease-modifying treatments target only the inflammatory process. They are ineffective in the progressive stage, leaving the science of disease progression unsolved. Here, the requirement is for strategies that promote remyelination and prevent axonal loss. Pathological and experimental studies suggest that these processes are tightly linked, and that remyelination or myelin repair will both restore structure and protect axons. This review considers the basic and clinical biology of remyelination and the potential contribution of stem and precursor cells to enhance and supplement spontaneous remyelination.

Figures

Figure 1

Demyelination, axonal loss and disease progression in MS. (a) The early stage of relapsing–remitting MS is characterized by transient neurological deficits that return to normal and pathology dominated by demyelination and focal inflammation. However, as the disease progresses, neurological dysfunction becomes fixed and accumulates. The pathological correlate of the progressive phase of the disease is axonal loss. (b) The early events of demyelination and inflammation are believed to contribute to axonal loss by numerous mechanisms, including loss of oligodendrocyte/myelin-derived trophic and structural support. The schematic diagram shows a single oligodendrocyte (black and white) myelinating three axons (axon: purple; myelin: blue). Early in the course of MS, the oligodendrocyte is damaged resulting in the demyelination of the axon. The loss of oligodendrocyte ‘support’ contributes and culminates in the axonal loss as found in progressive MS.

Figure 2

Strategies to promote endogenous remyelination. A schematic showing (a) recruitment of OPCs into the demyelinated MS lesion, (b) promotion of OPC differentiation, maturation, engagement and remyelination of axons, and (c) removal of inhibitory signals within the chronic demyelinated lesion that prevent successful remyelination. Electron micrograph demonstrating remyelination of a demyelinated adult axon by an oligodendrocyte progenitor cell (courtesy of S. Chandran and W. F. Blakemore).

Figure 3

Promotion of myelin repair by exogenous cells. Cells may be derived from developmentally distinct stages: embryonic, foetal and adult. Two classes of cells have generated particular interest, each with their own benefits and drawbacks: NPCs and adult non-neural stem cells. NPCs may be generated by ex vivo manipulation from human embryonic stem cells, or directly from primary foetal or adult brain samples. Adult mesenchymal stem cells can be generated from readily accessible sources such as skin and bone marrow. Other cell types that are potentially capable of myelination include olfactory ensheathing cells and Schwann cells. Exogenous cells may promote remyelination directly or indirectly by differentiation into myelinating cells and/or promotion of endogenous remyelination. In addition, grafted cells can be neuroprotective by means independent of differentiation such as immune modulation and trophic support (see text for details).